FOLR1 ( Folate receptor alpha )

MIRV did not seem to impair or improve patient quality of life compared with investigator's choice of chemotherapy. The similar quality-of-life outcomes in the two treatment groups, combined with the previously reported higher efficacy of MIRV compared with single-agent chemotherapy, support MIRV as new treatment option for FRα-positive platinum-resistant ovarian cancer.

A significant proportion of LGSC express high FOLR1 levels supporting the development of clinical trials to investigate ADCs targeting FOLR1 as novel agents for treating this disease. In LGSC, high FOLR1 expression was associated with fewer MAPK pathway alterations, low PR expression, and p16 loss.

This review of trial data and pharmacology information for AIBW dosing of mirvetuximab soravtansine-gynx will help support its integration into the PROC treatment landscape. The review also discusses recommendations for prophylaxis, monitoring, and management of common AEs, including eye drop regimens to mitigate ocular events. Mirvetuximab soravtansine-gynx is an effective, novel agent for PROC that targets a newly established biomarker. Established interventions can help mitigate AEs and support the safe use of mirvetuximab soravtansine-gynx.

MIRV confers meaningful PFS benefit for a subset of individuals with HGSOC. Resistance may be associated with decreased FOLR1 target expression or payload resistance. FOLR1-targeted ADCs with a different payload should be evaluated for patients who progress on MIRV but retain high tumor FOLR1 expression.

Moreover, we identified potential new targets for endometrial cancer treatment and explored strategies to overcome ADC resistance, such as choosing combination therapy or developing a new generation of ADC drugs. Continuous research and innovation in this field hold promise for improving the survival and overall quality of life of patients with advanced endometrial cancer.

Furthermore, MIRV's therapeutic versatility extends to other FRα-positive tumors, such as endometrial and breast cancers, broadening its clinical relevance. Despite challenges such as accessibility and cost, MIRV represents a significant advancement in precision medicine, with potential to redefine prevention and treatment strategies for hereditary and sporadic cancers.

No abstract available

These data highlight the need for caution in antibody selection when developing immunohistochemistry-based assays, as some antibodies failed to cleanly and specifically identify FRα expression. We identified 2 antibodies appropriate for further investigation; however, as developed, these antibodies may overselect patients for treatment with FRα-targeted therapies.

This case report highlights an Aisan patient with ovarian cancer, who exhibited tolerance, recurrence, and progression after several prior lines of treatment. The application of Mirvetuximab Soravtansine, facilitated by positive FRα expression identified through IHC analysis, notably reduced tumor lesions and CA125 levels, achieving a complete response and maintaining low CA125 levels during treatment, underscoring its efficacy in treating platinum-resistant recurrent ovarian cancer.

Urticarial skin reactions following MOv18 IgE treatment were unlikely to result from allergic mechanisms or skin antigen recognition. The clinical presentation is consistent with infusion-related reactions commonly observed with monoclonal antibody treatments.

Novel insights into the tumor microenvironment, advances in antibody engineering to enhance immune-mediated effects, the emergence of ADCs, and several studies of anti-FRα agents combined with chemotherapy, targeted and immune therapy are offering new perspectives and treatment possibilities. Hence, we highlight key translational research and discuss several preclinical studies and clinical trials of interest, with an emphasis on agents and therapy combinations with potential to change future clinical practice.

FOLR1 is a stemness-associated biomarker for HCC, with serum levels serving as a diagnostic marker for HCC and a prognostic indicator for early-stage disease.

Notably, combinations of IMGN853 with topotecan or the anti-VEGF-A antibody B20 significantly reduced tumor growth compared to IMGN853 alone, while no significant effect was observed with olaparib. Our findings indicate that IMGN853 induces autophagic cell death, which contributes to its tumor-inhibiting effects. The identification of these effective combination therapies and the mechanisms behind FOLR1-mediated autophagic cell death could facilitate further clinical development of IMGN853.

In this study, we present data suggesting that the FOLR1 gene is highly expressed in (T)GCT cells in vitro and in vivo, and anti-FRα-targeting therapies should be investigated as a treatment modality in a subset of patients with TGCTs. Moreover, MIRV induced significant antitumor and bystander effects, thus showing its potential in further preclinical exploration and drug repurposing for a salvage treatment regime in refractory (T)GCT disease.

This resulted in an increased proportion of M1-TAMs, thereby improving the tumor immune microenvironment. Our study explores a nanotherapeutic strategy that enhances the biosafety of anti-glutamine metabolism therapy through folate targeting, effectively suppresses tumor cell proliferation, and enhances the anti-tumor immune response.

P1, N=12, Recruiting, Fred Hutchinson Cancer Center | Not yet recruiting --> Recruiting

P1, N=86, Completed, Shattuck Labs, Inc. | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Feb 2025 | Trial primary completion date: Nov 2024 --> Feb 2025

Although platinum-based chemotherapy, PARP inhibitors and bevacizumab have prolonged long term survival and increased the overall response rate for platinum-sensitive ovarian cancer (PSOC), the treatment options for platinum-resistant ovarian cancer (PROC) are still limited. Since mirvetuximab soravtansine (MIRV) received approval by the US Food and Drug Administration (FDA) as the first ADC for PROC in 2022, the development of novel ADCs for various targets in PROC has accelerated. In this review, we summarise the recent evidence and future prospects of ADCs targeting Folate Receptor alpha (FRα), mesothelin, cadherin-6, NaPi2b, human epidermal growth factor receptor 2 (HER2), dipeptidase 3 (DPEP3), B7-H4 (VTCN1), claudin-6 (CLDN6) and trophoblast antigen protein 2 (TROP2), in order to enhance our understanding of the clinical applications of ADCs and offer new insights for clinical practice and further research.

P2, N=125, Active, not recruiting, AbbVie | Trial completion date: Dec 2026 --> May 2026 | Trial primary completion date: Jun 2025 --> May 2026

We revealed that FOLR1 orchestrates the malignant advancement of GBM by stimulating the SRC/ERK1/2 signaling axis, underscoring its pivotal role in the pathogenesis of GBM.

P1/2, N=404, Recruiting, Genmab | Trial completion date: Apr 2026 --> Oct 2026 | Trial primary completion date: Oct 2025 --> Apr 2026

Furthermore, NSD2 or FOLR1 silencing decreased the expression of key glycolytic genes (HK2, TIGAR, and G6PD) by suppressing their promoter activity and weakening the interaction between FOLR1/H3K36me2 and these gene promoters. Our findings suggest that NSD2-mediated H3K36me2 recruits FOLR1 to promote PAH, and FOLR1 acts as a transcriptional factor to upregulate glycolytic gene expression in PAECs.

During IMI with pafolacianine, a nonfluorescent nodule is more likely to be SCC than AC. AC has a high probability of fluorescing because of higher expression of FRα or FRβ, or both.

P1, N=423, Recruiting, AbbVie | Trial completion date: Dec 2025 --> Feb 2027 | Trial primary completion date: Dec 2024 --> Feb 2027

These findings reveal actionable insights into targeted therapies, including immune checkpoint inhibitors and PARP inhibitors, which hold promise for improving outcomes in HGSOC. This synthesis of knowledge aims to bridge gaps in understanding HGSOC's multifaceted biology, enhance clinical decision-making, and foster the development of precision therapies.

MIRV has significant therapeutic effects in solid tumors, especially when combined with BEV. In platinum-tolerant tumors, the efficacy of MIRV is also considerable. Overall, MIRV is relatively safe in solid tumors, and adverse reactions are relatively rare and mild.

While initially intended to identify adenocarcinoma, IMI with pafolacianine targets a broad histological cross-section of malignant and nonmalignant primary and metastatic lesions in the lung. As real-world use expands, additional insight will continue to inform utility of pafolacianine in clinical practice and may broaden clinical applicability.

Moreover, the avid bivalent affibody molecule exhibited minimal inhibition by soluble antigen, whereas high-affinity bivalent antibody was inhibited by 97 ± 2%, which is indicative of serum inhibition of shed antigen. This work advances design principles for achieving expression-dependent tumor targeting via low-affinity, high-avidity ligands.

P2, N=79, Completed, AbbVie | Active, not recruiting --> Completed

The therapeutic lead radiopharmaceutical [131I]I-GMIB-2BD42 showed fast pharmacokinetics with specific retention in hFRα + tumours. In addition, we report therapeutic efficacy with no signs of toxicity. In this study, we successfully designed a new drug for RLT, overcoming previous limitations, such as high kidney retention, which could aid in revitalising FRα-targeted radiotherapy.

However, the treatment is associated with a high incidence of gastrointestinal and hematological AEs, raising the need for careful patient selection. Further studies are required to refine the therapeutic regimen and ensure an optimal balance between efficacy and safety.

Notably, NIR-II FLT imaging demonstrates superior accuracy (90%) and consistency in defining tumor margins compared to NIR-II FL imaging (58%) in both SK-OV-3 tumor-bearing mice and clinical tumor samples. These findings underscore the potential of NIR-II FLT imaging as a quantitative tool for guiding surgical tumor margin detection.

•Mirvetuximab soravtansine (MIRV) is used in the treatment of FRα positive, platinum-resistant epithelial ovarian cancer.•MIRV is associated with ocular events, leading to dose delays, dose reductions, and discontinuations of chemotherapy.•Mitigation strategies to prevent treatment disruption have historically relied on corticosteroid and lubricating drops.•Dehydrated amniotic membrane patch to treat MIRV related ocular events is a novel therapeutic option.

Our results highlight a need for standardized protocols for FRα testing to ensure accurate biomarker evaluation across varied clinical settings. The heterogeneity in FRα expression, influenced by tumor histology and anatomical origin, warrant further investigation to optimize therapeutic outcomes.

MIRV as ≥3L treatment in heavily pretreated recurrent FRα-positive PSOC demonstrated notable efficacy and tolerable safety, including among those with prior PD on or within 30 days of PARPi. (Funding, ImmunoGen, Inc; NCT05041257).

We identified a gene expression signature correlated to high FRα expression and OC prognosis, which may be used to refine therapeutic strategies targeting FRα in OC. These findings warrant validation in larger cohorts.

We summarize the mechanisms of the action of various therapeutic strategies based on FRα, including MABs (monoclonal antibodies), ADCs (antibody-drug conjugates), FDCs (folate-drug conjugates), SMDCs (small molecule-drug conjugates), vaccines, and CAR-T (chimeric antigen receptor T) cells, and present the most significant clinical trials of some FRα-based drugs. Furthermore, we discuss the pros and cons of different FR-based therapies, highlighting mirvetuximab soravtansine (MIRV) as the currently most promising EOC-targeting drug.

Our validation strategy highlights that assays comprehensively characterizing CAR functionality and binding specificity complement each other. Thereby, critical specificity considerations can be addressed early in the development process to overcome current limitations for future CAR T cell therapies.

P1, N=423, Recruiting, ImmunoGen, Inc. | N=227 --> 423

P2, N=90, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P3, N=453, Completed, ImmunoGen, Inc. | Active, not recruiting --> Completed

This report emphasizes the crucial role of meticulous sampling and histopathologic examination of the fallopian tube, including the fimbriae, in all salpingectomy specimens. Furthermore, the case highlights the broad spectrum of morphologies encountered in HGSC, including mucinous differentiation. HGSC should be in the differential diagnosis when encountering mucin-producing high-grade carcinoma.